Biodegradable copolymer and thermosensitive material

ABSTRACT

The disclosed is a biodegradable copolymer, an amphiphilic diblock copolymer, composed of a hydrophilic segment and a hydrophobic segment. The hydrophilic segment is an endcapped PEG or derivatives thereof. The hydrophilic segment is a random polymer polymerized of lactone or cyclic C 3 -C 6  molecule and lactic acid/glycolic acid. There is no coupling agent between the hydrophilic and hydrophobic segments, and the biodegradable copolymer is formed by one-pot ring-opening polymerization. The biodegradable copolymer can be dissolved in water to form a thermosensitive material having a phase transfer temperature of 25 to 50° C., thereby being applied to biological activity factor delivery, tissue engineering, cell culture and biological glue.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of pending U.S. patent applicationSer. No. 12/395,495, filed Feb. 27, 2009 and entitled BiodegradableCopolymer and Thermosensitive Material, which in turn claims priority ofTaiwan Patent Application No. 097111275, filed on Mar. 28, 2008, andTaiwan Patent Application No. 097141336, filed on Oct. 28, 2008, theentirety of which is incorporated by reference herein

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a biodegradable copolymer, and inparticular relates to the thermosensitive property of a solutionthereof.

2. Description of the Related Art

For hard tissue recovery/surgery, fixation of bone fragments in acomminuted or joint fracture is one of the most challenging procedures.For fixation, a K-pin, a bone nail, or a steel wire may be utilized,however, ablation of soft tissue adhered on the bone fragments isnecessary before using the fixation materials. Therefore, bloodcirculation and bone healing are degraded, and the bone fragmentsincrease risk of destruction into a more powdery form. Commerciallyavailable bone cement (e.g. polymethylmethacrylate), serves as anadhesion for bone fragments or a filler for bone cavities. Thebiological inert bone cement rarely causes allergic reactions and cannotbe absorbed by the human body, such that complete bone healing of thebone fragments fixed by the bone cement is difficult. As such, the bonecement is not suitable for fracture caused by trauma. For orthopedist,an absorbable bioadhesion material for bone fragment adhesion to improvebone healing is demanded.

For soft tissue recovery/surgery, an endoscope is utilized for minimalinvasive surgery, specifically in shoulder reconstructive surgery.Conventional techniques utilize drills to drill a hole through theshoulder bone to seam bone and tendons, thereby consuming time.Recently, sutureless anchors and knotless anchors have been popularlyutilized to become mainstream techniques for saving operating time dueto inconvenience, and further prevent abrasion and tissue reactioncaused from residue knots. If the sutureless anchor is utilized for anablated tissue, the stress of the anchor will be concentrated on theablated tissue to form a bulge, such that the bioadhesion is utilized toadhere to the ablated tissues to accelerate tissue regeneration. If theknotless anchor is utilized for the ablated tissue, the healing effectwill be dependant upon the operating skill of the surgeon, anchorstrength, and degree of tissue regeneration. Meanwhile, the bioadhesionis utilized to adhere to the ablated tissues to improve the healingeffect.

For a hip joint, avascular necrosis (AVN) is mainly found in youths andelderly. Although an artificial hip joint can replace a hip joint withAVN, early treatment can also be utilized to cure 75% AVN patients. Thepresent treatment for AVN is core decompression, wherein a hole isdrilled from the edge to the front end of the thighbone, and autogenicbone grafts full of veins are implanted into the drilled hole, such thatblood is able to flow to the necrosis zone for bone regeneration.However, the described treatment needs an additional operation tocollect the autogenic bone grafts from the patient's body, therebyextending the healing period. Note also that a combination ofbioadhesion and medicine can be implanted into the thighbone tostimulate veins and bone regeneration following degradation of thebioadhesion to immediately release the medicine.

Meanwhile, delivery of biological activity factors such as medicines,cells, growth factors, and genes are important in biological medicineapplications such as medicine therapy, gene therapy, and tissueengineering. The materials which serve as a delivery carrier mustpossess bio-compatibility and biodegrability for an implanting in vivo.In addition, the material should easily flow in vitro to evenly mix withmedicine. The material which is subsequently injected into a body by acatheter or an endosope, should transform to a gel after injection forfixing activity factors in the predetermined tissue regions, and slowlyreleasing the activity factors to complete treatment. Presently, asuitable delivery material is rare. Some materials form a gel throughchemical reaction, thereby influencing the activity of the biologicalactivity factors or damaging the implanted tissue region. Some materialshave excellent thermosensitivity and gel formability but poorbiodegradability, thereby preventing applicability for an implantationin vivo.

In U.S. Pat. No. 5,514,380, Song discloses a biodegradable copolymer gelwhich serves as a medicine delivery matrix. The copolymer is composed ofhydrophilic and hydrophobic segments, the hydrophilic segment isprimarily polyethyleneoxide (PEO), and the hydrophobic segment ispolylactide (PLA), polyglycolide (PGA), polylactide-glycolide (PLGA), orpolycaprolactone (PCL). The multi block copolymer is applied to a drugreleasing carrier. However, the patent discloses a multi block copolymersuch as ABABAB, wherein A means hydrophilic segment and B meanshydrophobic segment, without disclosing the thermosensitive property.Furthermore, the patent also fails to disclose that the hydrophobicsegment is a random copolymer of lactone or cyclic C₃-C₆ molecule andlactic acid/glycolic acid.

MacroMed Corporation has four U.S. patents: U.S. Pat. No. 5,702,717,U.S. Pat. No. 6,004,573, U.S. Pat. No. 6,117,949, and U.S. Pat. No.6,201,072. The patents disclose biodegradable thermosensitive triblockcopolymer, such as ABA or BAB. A hydrophilic segment A is a polyethyleneglycol (PEG), and a hydrophobic segment B is a polyester. Thebiodegradable triblock copolymer has a molecular weight of 2000 to 4990g/mol, and a reverse thermal gelation. The hydrogel, prepared from thecopolymer, can be mixed with a medicine at room temperature. The mixturewill transform to a gel after being injected into homoiothermic animals,and the medicine release rate is determined by the hydrolysis rate ofthe gel in vivo. The hydrolysis product of the gel is free ofbio-toxicity. However, the patents do not disclose the thermosensitivediblock copolymer AB, and that the hydrophobic segment is a randomcopolymer of lactone or cyclic C₃-C₆ molecule and lactic acid/glycolicacid.

In U.S. Pat. Nos. 6,451,346 and 6,004,573, Amgen Corporation disclosesABA and AB block copolymers with pH and thermo sensitivities. Thehydrophilic segment A of the copolymer is PEG, and the hydrophilicsegment B is PLA or PLGA. However, the patent does not disclose that thehydrophobic segment is a random copolymer of lactone or cyclic C₃-C₆molecule and lactic acid/glycolic acid. Furthermore, succinic anhydrideis necessary to be a crosslinking agent between the hydrophobic andhydrophilic segments, and is different from the direct ring-openingproduct of the invention.

In U.S. Pat. No. 7,087,244, Byeongmoon Jeong discloses triblockcopolymers such as ABA and BAB with thermosensitivity. The copolymersare applied as a biological activity factor release carrier. However,the patent does not disclose that the hydrophobic segment is a randomcopolymer of lactone or cyclic C₃-C₆ molecule and lactic acid/glycolicacid, and the copolymer thereof is triblock not diblock.

In U.S. Pat. Nos. 5,410,016, 5,567,435, and 5,986,043, Hubbell disclosesa diblock copolymer AB system. The initiator thereof is a photoinitiator or a thermo initiator. In U.S. Pat. No. 5,410,016, thehydrophobic segment B is poly(α-hydroxy acid) (PHA), poly(glycolic acid)(PGA), PLA, or polylactone such as poly(ε-caprolactone) (PCL),poly(δ-valerolactone) (PVL), or poly(λ-butyrolactone) (PBL). However,the patent does not disclose that the hydrophobic segment is a randomcopolymer of lactone or cyclic C₃-C₆ molecule and lactic acid/glycolicacid. Alternatively, in the U.S. Pat. Nos. 5,567,435, and 5,986,043, thediblock copolymer has a PEG center with extension such as PHA, PGA, PLA,polylactone, poly(amino acid), polyanhydride, poly(orthoester),poly(orthocarbonate), or poly(phosphoester). However, similarly, thepatents also fail to disclose that the hydrophobic segment is a randomcopolymer of lactone or cyclic C₃-C₆ molecule and lactic acid/glycolicacid. In addition, U.S. Pat. No. 6,060,582 discloses a photopolymerizeddiblock copolymer with three segments B, L, and P. P is an ethylenesegment for photo initiation, B is PEG, and L is PHA, acrylic estermonomer or oligomer. The P segment and L segment are first coupled toform a hydrophobic segment, and the hydrophobic segment is then coupledwith the B segment. Although the diblock copolymer in U.S. Pat. No.6,060,582 can be applied for anti-adhesion after surgery, releasingmedicine, tissue adhesion, and preventing cell adhesion to tissue, itstill fails to disclose that the hydrophobic segment is a randomcopolymer of lactone or cyclic C₃-C₆ molecule and lactic acid/glycolicacid.

In U.S. Pat. No. 5,514,380, Samyang Corporation discloses a copolymerwith hydrophilic and hydrophobic segments. The hydrophilic segment isPEO and the hydrophobic segment is PLA, PGA, PLGA, or PCL. The copolymeris a thermoplastic biodegradable gel. However, the patent fails todisclose thermosensitivity, and also fails to disclose that thehydrophobic segment is a random copolymer of lactone or cyclic C₃-C₆molecule and lactic acid/glycolic acid.

In U.S. Pat. No. 6,136,333, Life Medical Sciences Corporation disclosesblock copolymers AB and ABA. Segment A is polyester, segment B ispolyoxyalkylene polymer unit, segments A and B have a ratio of 1:0.1 to1:100, and the segments A and B have hexamethylene diisocyanate (HMDI)as crosslinking agent therebetween. The block copolymers serve asanti-adhesion material. However, the patent does not disclose thethermosensitivity, and fails to disclose that the hydrophobic segment isa random copolymer of lactone or cyclic C₃-C₆ molecule and lacticacid/glycolic acid.

In U.S. Pat. No. 6,841,617, Battle Memorial Institute discloses an An(B)block copolymer that is a thermosensitive and biodegradable gel, whereinA is PEG and B is polyester. However, the polymerization thereof isthrough grafting, and it also fails to disclose that the hydrophobicsegment is a random copolymer of lactone or cyclic C₃-C₆ molecule andlactic acid/glycolic acid.

In U.S. Pat. No. 7,094,810, Lapopharm Corporation discloses a blockcopolymer AB. The hydrophilic segment A is PEO, and an the hydrophobicsegment B is poly(butyl(alkyl)acrylate-co-(alkyl)acrylic acid. However,the patent fails to disclose that the hydrophobic segment is a randomcopolymer of lactone or cyclic C₃-C₆ molecule and lactic acid/glycolicacid.

In U.S. Pat. No. 7,153,520, Samyang Corporation discloses an amphiphilicdiblock copolymer that is a slow-degradable drug delivery material,wherein the hydrophilic segment is PEG, and hydrophobic is PLA, PCL,PLGA, PLDO, poly(lactide-co-p-dioxanone), poly(orthoester),polyanhydride, poly(amino acid), and polycarbonate. However, the patentdoes not disclose that the copolymer is thermosensitive.

In U.S. Pat. No. 4,188,373, Krezanoski discloses an aqueous solutionPEO-PPO polymer with a phase transfer temperature of 25° C. to 40° C.,wherein the hydrogel system can be applied as a drug delivery carrier.However, the polymer material thereof has no hydrophobic segment.

In U.S. Pat. No. 4,474,752, Haslam discloses a medicine delivery system,wherein the medicine is liquid at room temperature and transforms to asemisolid or gel at body temperature. The hydrogel has 40-80% PEO and20-60% PPO and a molecular weight of 7,000 to 50,000. However, thehydrogel does not have a hydrophobic segment.

In the Chem. Commun. 2001, 1516-1517, Jeong discloses a thermosensitivecopolymer PLGA-g-PEG. The backbone of the polymer is PLGA and the sidechains PEG are grafted on the backbone, wherein the lactide, glycolicacid, and PEG have a molar ratio of 3.2:1:2.8. The copolymer has amolecular weight of 9,300, a weight percent in water of 25 wt %, and aphase transfer temperature of 30° C. However, the paper fails todisclose that the hydrophobic segment is a random copolymer of lactoneor cyclic C₃-C₆ molecule and lactic acid/glycolic acid.

In the Polymer 2000, 41, 7091-7097, Lee discloses an amphiphilic polymermaterial with thermosensitivity. The polymer material is copolymerizedof 2-ethyl-2-oxazoline and E-caprolactone. However, the paper does notdisclose that the hydrophobic segment is a random copolymer of lactoneor cyclic C₃-C₆ molecule and lactic acid/glycolic acid.

In the Journal of Controlled Release 2002, 80, 69-77, Kim discloses athermosensitive composite polymer hydrogel, wherein the hydrogel isphotopolymerized of polyethylene oxide-polypropylene oxide andhyaluronic acid. The hydrogel serves as a human growth hormone deliverycarrier to study drug release kinetics of related medicines andproteins. However, the polymer hydrogel does not have a hydrophobicsegment.

In 1999, You Han Bae utilized condensation of PEG and PLA withcarboxylic acid terminals to obtain a thermosensitive block copolymerPLA-PEG-PLA. The PEG has a molecular weight (Mn) of 1,000 to 2,000, andthe PLA has a molecular weight of 820 to 3,150. The 1 wt % PLA-PEG-PLAaqueous solution has a low critical solution temperature (LCST) of 27°C. to 45° C., the aqueous solution does not transform into a gel or asemisolid, and the LCST is modified by tuning the length of thehydrophobic segment PLA. However, the thermosensitive polymer is not adiblock copolymer, and the hydrophobic segments thereof were not randomcopolymers of lactone or cyclic C₃-C₆ molecule and lactic acid/glycolicacid.

BRIEF SUMMARY OF THE INVENTION

The invention discloses a biodegradable copolymer, having a generalformula: A-B; wherein A is a hydrophilic segment, having a generalformula:

R₁ is C₁₋₈ alkyl; R₂ is ethyl, C₁₋₈ alkyl ethyl, C₁₋₈ alkoxyl ethyl, orcombinations thereof; and n is an integral of 5-20; and B is ahydrophobic segment, having a general formula:

R₃ is hydrogen or methyl; R₄ is a linear, branched or cyclic, saturatedor unsaturated C₂-C₅ alkanediyl group optionally comprising one or morehetero atoms including O, S or N; J is C═O, C═S, C—CHO, C═NH, or C═NR₅,wherein R₅ is C₁-C₃ alkyl group; K is O, S, C—CHO, NH, or NR₆, whereinR₆ is C₁-C₃ alkyl group; x is an integral of 5-20; and y is an integralof 5-20.

The invention also provides a thermosensitive material, comprising waterand the biodegradable copolymer as described above dissolved in thewater to form a solution, wherein the hydrophobic segment B aggregatesto form micelles.

A detailed description is given in the following embodiments withreference to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention can be more fully understood by reading thesubsequent detailed description and examples with references made to theaccompanying drawings, wherein:

FIG. 1 is an NMR spectrum of mPEG-PPLA in one example of the invention;

FIG. 2 is a micelle diameter distribution diagram of mPEG-PPLA in oneexample of the invention;

FIG. 3 is a critical micelle concentration diagram of mPEG-PPLA in oneexample of the invention;

FIG. 4 is a UV transmittance versus temperature diagram of mPEG-PPLA,mPEG-PVLA, and mPEG-PCLA in examples of the invention;

FIG. 5 is a viscosity versus temperature diagram of mPEG-PPLA,mPEG-PVLA, and mPEG-PCLA in examples of the invention;

FIG. 6 is an NMR spectrum of mPEG-PVLA in one example of the invention;

FIG. 7 is a micelle diameter distribution diagram of mPEG-PVLA in oneexample of the invention;

FIG. 8 is a critical micelle concentration diagram of mPEG-PVLA in oneexample of the invention;

FIG. 9 is a medicine release curve of cyclosporine corresponding todifferent concentrations of mPEG-PVLA solution in one example of theinvention;

FIG. 10 is an NMR spectrum of mPEG-PCLA in one example of the invention;

FIG. 11 is a micelle diameter distribution diagram of mPEG-PCLA in oneexample of the invention;

FIG. 12 is a critical micelle concentration diagram of mPEG-PCLA in oneexample of the invention;

FIG. 13 is a medicine release curve of cyclosporine corresponding todifferent concentrations of mPEG-PCLA solution in one example of theinvention;

FIG. 14 is an NMR spectrum of mPEG-PSLA in one example of the invention;

FIG. 15 is a micelle diameter distribution diagram of mPEG-PSLA in oneexample of the invention;

FIG. 16 is a critical micelle concentration diagram of mPEG-PSLA in oneexample of the invention;

FIG. 17 is a UV transmittance versus temperature diagram of mPEG-PSLA inexamples of the invention;

FIG. 18 is a viscosity versus temperature diagram of mPEG-PSLA inexamples of the invention;

FIG. 19 is a Sol-Gel-Sol related to temperature and concentration ofmPEG-PSLA in examples of the invention;

FIG. 20 is an NMR spectrum of mPEG-PITLA in one example of theinvention;

FIG. 21 is a micelle diameter distribution diagram of mPEG-PITLA in oneexample of the invention;

FIG. 22 is a critical micelle concentration diagram of mPEG-PITLA in oneexample of the invention;

FIG. 23 is a UV transmittance versus temperature diagram of mPEG-PITLAin examples of the invention;

FIG. 24 is a viscosity versus temperature diagram of mPEG-PITLA inexamples of the invention;

FIG. 25 is a UV transmittance versus temperature diagram of mPEG-PNLA,mPEG-PPDLA, mPEG-PTTLA, mPEG-POTLA, mPEG-PACTLA, mPEG-PTCALA in examplesof the invention; and

FIG. 26 is a viscosity versus temperature diagram of mPEG-PLA in onecomparative example of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The following description is of the best-contemplated mode of carryingout the invention. This description is made for the purpose ofillustrating the general principles of the invention and should not betaken in a limiting sense. The scope of the invention is best determinedby reference to the appended claims.

The invention discloses a biodegradable copolymer having a generalformula as shown in Formula 1. The hydrophilic segment A has a generalformula as shown in Formula 2. In Formula 2, R₁ is C₁₋₈ alkyl. R₂ isethyl, C₁₋₈ alkyl ethyl, C₁₋₈ alkoxyl ethyl, or combinations thereof. nis an integral of 5-20. The hydrophobic segment B has a general formulaas shown in Formula 3. In Formula 3, R₃ is hydrogen or methyl. R₄ is alinear, branched or cyclic, saturated or unsaturated C₂-C₅ alkanediylgroup; this alkanediyl group can optionally be interrupted by one ormore hetero atoms such as O, S or N. J is C═O, C═S, C—CHO, C═NH, orC═NR₅, wherein R₅ is C₁-C₃ alkyl group. K is O, S, C—CHO, NH, or NR₆,wherein R₆ is C₁-C₃ alkyl group. x is an integral of 5-20. y is anintegral of 5-20.

Manufacturing of the biodegradable copolymer is described as below.First, since an equivalent ratio of alcohol and ethylene glycol orderivative thereof is reacted under an acid condition, therefore oneterminal of the ethylene glycol is endcapped by an alkoxy group. In oneembodiment, the ethylene glycol derivative can be a C₁₋₈ alkyl ethyleneglycol such as methyl ethylene glycol, or a C₁₋₈ alkoxy ethylene glycolsuch as methoxy ethylene glycol. The alcohol is C₁₋₈ alcohol. In oneembodiment, the alcohol is methanol. In one embodiment, the methoxyendcapped poly ethylene glycol, the hydrophilic segment of thebiodegradable copolymer, has a molecular weight of 300 to 1000.

Next, lactic acid, glycolic acid, or the precursors thereof are selectedas a necessary monomer of the hydrophobic segment. The lactic acid canbe any type of enantiomers or mixtures thereof, such as D-lactic acid,L-lactic acid, or DL-lactic acid. The lactic acid precursor can belactide of any type of enantiomers or mixtures thereof, such asD-lactide, L-lactide, or DL-lactide. The lactide has a general formulaas shown in Formula 4. The glycolic acid precursor includes glycolide asshown in Formula 5.

In addition, the lactone or the cyclic C₃-C₆ molecule can be selected asone necessary monomer of the hydrophobic segment. Suitable lactonesincludes β-propiolactone, γ-thiobutyrolactone, δ-valerolactone, orε-caprolactone. Suitable cyclic C₃-C₆ molecule includes 2-Iminothiolanehydrochloride(2-IT), (4R)-(−)-2-Thioxo-4-thiazolidinecarboxylic acid,(−)-2-Oxo-4-thiazolidinecarboxylic acid, DL-N-Acetylhomocysteinethiolactone, 5-Thiazolecarboxaldehyde, γ-butyrolactam, or1-Methyl-2-pyrrolidinone(NMP).

Subsequently, the endcapped polyethylene glycol or derivatives thereof,lactic acid and/or glycolic acid and precursor thereof, lactone, orcyclic C₃-C₆ molecule are mixed and reacted to form a diblock copolymerby ring-opening polymerization. The copolymer is a biodegradablematerial, the hydrophilic segment is endcapped polyethylene glycol orderivatives thereof, and the hydrophobic segment is copolymerized oflactic acid/glycolic acid (or derivatives thereof), lactone, or cyclicC₃-C₆ molecule. In one embodiment, the lactic acid/glycolic acid molarratio (x in Formula 3) is greater than or equal to the lactone or cyclicC₃-C₆ molecule molar ratio (y in formula 3). In one embodiment, thelactic acid/glycolic acid and the lactone or cyclic C₃-C₆ molecule havea molar ratio (x:y) between 50:50 to 90:10.

Because the manufacturing of the biodegradable polymer of the inventionis by one-pot reaction without any additional crosslinking agent orcoupling agent between the hydrophilic and hydrophobic segments,synthesis periods and steps are reduced.

The described biodegradable copolymer is further dissolved in water toform a thermosensitive material, so that properties may be measured,e.g. critical micelle concentration, micelle diameter, gelling time,hemolysis, adhesion strength, and drug release. In one embodiment, thebiodegradable copolymer and water have a weight ratio of 2:98 to 40:60.In another embodiment, the biodegradable copolymer and water have aweight ratio of 15:85 to 30:70. If the weight ratio is less than 2:98,the solution cannot be gelled. On the other hand, the biodegradablecopolymer cannot be totally dissolved in water if the weight ratio isgreater than 40:60 or 30:70. As known from invention experiments, thecritical micelle concentration of the solution is about 0.003 wt % to0.07 wt % with a micelle diameter of 5 nm to 500 nm. In one embodiment,the described thermoseensitive material has a phase transfer temperatureof 25° C. to 50° C. In one embodiment, the described thermoseensitivematerial has a phase transfer temperature of 30° C. to 40° C. Thethermosensitive material is liquid when the temperature is lower thanthe phase transfer temperature, and forms a hydrogel when thetemperature is higher than the phase transfer temperature. According tothe measurement, the gelling time of the thermosensitive material isless than 30 seconds. The hydrogel has excellent adhesion strength,non-hemolysis, and high biocompatibility. The phase transfer isreversible, meaning that the hydrogel will return to a liquid phase ifthe temperature is reduced to lower than the phase transfer temperature.In addition, the hydrophobic segment of the copolymer can be hydrolysisto a harmless compound for a human body. The hydrophilic segment of thecopolymer can be dissolved in water and then egested by human body. Indrug release experiments, the thermosensitive material of the inventionreleases drug in different ratios corresponding to the concentrationthereof, and it can be applied as a long-acting medicine carrier.Accordingly, the thermosensitive material can be applied to biologicalactivity factor delivery, tissue engineering, cell culture, orbiological glue, wherein the biological activity factor includesmedicine, cell, growth factor, inorganic salt, ceramic material,poly-(amino acid), peptide, protein, gene, DNA sequence or RNA sequence.The biological glue is applied in a cell organism, tissue, implantsurface adhesion, soft and hard tissue recovery, or an implant carrierfiller, or a hemostatic glue. The thermosensitive material type may beapplied through injection, pastille, powder, gel, solution, or oralliquid

EXAMPLES AND COMPARATIVE EXAMPLES Example 1 Copolymer of MethoxyEndcapped Polyethylene Glycol and Lactide/β-Propiolactone RandomCopolymer, Hereinafter mPEG-PPLA)

21.14 g of methoxy endcapped polyethylene glycol (mPEG, Molecular Weightis 550 g/mol), 50 g of lactide, and 18.77 g of β-propiolactone weresubsequently charged in an anhydrous reactor, and the reactortemperature was slowly increased until the substances were totallydissolved. The temperature was continuously increased to 160° C., and42.0 μL stannous catalyst (stannous 2-ethylhexanoate) was added in thereactor to process polymerization at 160° C. for 8 hours. The reactionis shown in Formula 6. The reaction result was precipitated in ethylether/hexane (volume ratio is 1:9) as a semitransparent gel. Thesemitransparent gel was washed three times to remove monomers and thendried in a vacuum at 40° C. for 24 hours to obtain product mPEG-PPLA.

The copolymer mPEG-PPLA had an NMR spectrum as shown in FIG. 1, and adiameter analysis with instrument Zetasizer 1000H as shown in FIG. 2.The mPEG-PPLA dissolved in water is the thermosensitive material of theinvention, and the critical micelle concentration analysis is shown inFIG. 3, the UV transmittance related to temperature is shown in FIG. 4,and the viscosity related to temperature is shown in FIG. 5. When themPEG-PPLA liquid transforms to hydrogel, its UV transmittance wasreduced. The thermosensitive material was a flowable transparentsolution at a low temperature, a semi-transparent solution with higherviscosity at 25° C., and a non-flowable opaque hydrogel at 40° C. Thegelling time of the mPEG-PPLA at 37° C. measured in a water sink wasabout 27.2 seconds. The hydrogel had adhesion strength of 52 gf/mm²,which is better than that of a commercially available fibrin glue (about49 gf/mm²).

Example 2 Copolymer of Methoxy Endcapped Polyethylene Glycol andLactide/δ-Valerolactone Random Copolymer, Hereinafter mPEG-PVLA)

17.03 g of methoxy endcapped polyethylene glycol (mPEG, Molecular weightis 550 g/mol), 33.6 g of lactide, and 10.0 g of δ-valerolactone weresubsequently charged in an anhydrous reactor, and the reactortemperature was slowly increased until the substances were totallydissolved. The temperature was continuously increased to 160° C., and34.0 μL stannous catalyst (stannous 2-ethylhexanoate) was added in thereactor to process polymerization at 160° C. for 8 hours. The reactionis shown in Formula 7. The reaction result was precipitated in ethylether/hexane (volume ratio is 1:9) as a semitransparent gel. Thesemitransparent gel was washed three times to remove monomers and thendried in vacuum at 40° C. for 24 hours to obtain product mPEG-PVLA.

The copolymer mPEG-PVLA has an NMR spectrum as shown in FIG. 6, and adiameter analysis with instrument Zetasizer 1000H as shown in FIG. 7.The mPEG-PVLA dissolved in water is the thermosensitive material of theinvention, the critical micelle concentration analysis is shown in FIG.8, the UV transmittance related to temperature is shown in FIG. 4, andthe viscosity related to temperature is shown in FIG. 5. When themPEG-PVLA liquid transformed to hydrogel, its UV transmittance wasreduced. The thermosensitive material was a flowable transparentsolution at a low temperature, a semi-transparent solution with higherviscosity at 25° C., and a non-flowable opaque hydrogel at 40° C. Thegelling time of the mPEG-PVLA at 37° C. measured in a water sink wasabout 27.5 seconds. The hydrogel had adhesion strength of 58 gf/mm²,which is better than that of commercially available fibrin glue (about49 gf/mm²). The medicine release experiment of cyclosporinecorresponding to different concentrations of mPEG-PVLA solution is shownin FIG. 9. The thermosensitive material mPEG-PVLA solution is suitablefor biological activity factor delivery such as medicine release.

Example 3 Copolymer of Methoxy Endcapped Polyethylene Glycol andLactide/ε-Caprolactone Random Copolymer, HEREINAFTER mPEG-PCLA

17.62 g of methoxy endcapped polyethylene glycol (mPEG, Molecular weightis 550 g/mol), 33.6 g of lactide, and 11.4 g of ε-caprolactone weresubsequently charged in an anhydrous reactor, and the reactortemperature was slowly increased until the substances were totallydissolved. The temperature was continuously increased to 160° C., and35.0 μL stannous catalyst (stannous 2-ethylhexanoate) was added in thereactor to process polymerization at 160° C. for 8 hours. The reactionis shown in Formula 8. The reaction result was precipitated in ethylether/hexane (volume ratio is 1:9) as a semitransparent gel. Thesemitransparent gel was washed three times to remove monomers and thendried in vacuum at 40° C. for 24 hours to obtain product mPEG-PCLA.

The copolymer mPEG-PCLA had an NMR spectrum as shown in FIG. 10, and adiameter analysis with instrument Zetasizer 1000H as shown in FIG. 11.The mPEG-PCLA dissolved in water is the thermosensitive material of theinvention, the critical micelle concentration analysis is shown in FIG.12, the UV transmittance related to temperature is shown in FIG. 4, andthe viscosity related to temperature is shown in FIG. 5. When themPEG-PCLA liquid transformed to hydrogel, its UV transmittance wasreduced. The thermosensitive material was a flowable transparentsolution at a low temperature, a semi-transparent solution with higherviscosity at 25° C., and a non-flowable opaque hydrogel at 40° C. Thegelling time of the mPEG-PCLA at 37° C. measured in a water sink wasabout 29.2 seconds. The hydrogel had adhesion strength of 100 gf/mm²,which is better than that of commercially available fibrin glue (about49 gf/mm²). The medicine release experiment of cyclosporinecorresponding to different concentrations of mPEG-PCLA solution is shownin FIG. 13. The thermosensitive material mPEG-PCLA solution is suitablefor biological activity factor delivery such as medicine release.

Example 4 Copolymer of Methoxy Endcapped Polyethylene Glycol andLactide/γ-Thiobutyrolactone Random Copolymer, Hereinafter mPEG-PSLA)

18.43 g of methoxy endcapped polyethylene glycol (mPEG, Molecular weightis 550 g/mol), 40 g of lactide, and 7.083 g of γ-thiobutyrolactone weresubsequently charged in an anhydrous reactor, and the reactortemperature was slowly increased until the substances were totallydissolved. The temperature was continuously increased to 160° C., and26.026 μL stannous catalyst (stannous 2-ethylhexanoate) was added in thereactor to process polymerization at 160° C. for 8 hours. The reactionis shown in Formula 9. The reaction result was precipitated in ethylether/hexane (volume ratio is 1:9) as a semitransparent gel. Thesemitransparent gel was washed three times to remove monomers and thendried in vacuum at 40° C. for 24 hours to obtain product mPEG-PSLA.

The copolymer mPEG-PSLA had an NMR spectrum as shown in FIG. 14, and adiameter analysis with instrument Zetasizer 1000H as shown in FIG. 15.The mPEG-PSLA dissolved in water is the thermosensitive material of theinvention, the critical micelle concentration analysis is shown in FIG.16, the UV transmittance related to temperature is shown in FIG. 17, andthe viscosity related to temperature is shown in FIG. 18. Sol-Gel-Solrelated to temperature and concentration is shown in FIG. 19. When themPEG-PSLA liquid transformed to hydrogel, its UV transmittance wasreduced. The thermosensitive material was a flowable transparentsolution at a low temperature, a semi-transparent solution with higherviscosity at 25° C., and a non-flowable opaque hydrogel at 46° C. Thegelling time of the mPEG-PSLA at 37° C. measured in a water sink wasabout 11.83 seconds.

Example 5 Copolymer of Methoxy Endcapped Polyethylene Glycol andLactide/2-Iminothiolane Hydrochloride Random Copolymer, HereinaftermPEG-PITLA

2.03 g of methoxy endcapped polyethylene glycol (mPEG, Molecular weightis 550 g/mol), 4.185 g of lactide, and 1 g of 2-Iminothiolanehydrochloride were subsequently charged in an anhydrous reactor, and thereactor temperature was slowly increased until the substances weretotally dissolved. The temperature was continuously increased to 200°C., and 2.886 μL stannous catalyst (stannous 2-ethylhexanoate) was addedin the reactor to process polymerization at 200° C. for 4 hours. Thereaction is shown in Formula 10. The reaction result was precipitated inethyl ether/hexane (volume ratio is 1:9) as a semitransparent brown gel.The semitransparent gel was washed three times to remove monomers andthen dried in vacuum at 40° C. for 24 hours to obtain productmPEG-PITLA.

The copolymer mPEG-PITLA had an NMR spectrum as shown in FIG. 20, and adiameter analysis with instrument Zetasizer 1000H as shown in FIG. 21.The mPEG-PITLA dissolved in water is the thermosensitive material of theinvention, the critical micelle concentration analysis is shown in FIG.22, the UV transmittance related to temperature is shown in FIG. 23, andthe viscosity related to temperature is shown in FIG. 24. When themPEG-PITLA liquid transformed to hydrogel, its UV transmittance wasreduced. The thermosensitive material was a flowable transparentsolution at a low temperature, a semi-transparent solution with higherviscosity at 25° C., and a non-flowable opaque hydrogel at 40° C.

Example 6 Copolymer of Methoxy Endcapped Polyethylene Glycol andLactide/N-Methyl-2-Pyrrolidone Random Copolymer, Hereinafter mPEG-PNLA

7.99 g of methoxy endcapped polyethylene glycol (mPEG, Molecular weightis 550 g/mol), 17.43 g of lactide, and 3 g of N-Methyl-2-Pyrrolidonewere subsequently charged in an anhydrous reactor, and the reactortemperature was slowly increased until the substances were totallydissolved. The temperature was continuously increased to 160° C., and11.37 μL stannous catalyst (stannous 2-ethylhexanoate) was added in thereactor to process polymerization at 160° C. for 8 hours. The reactionis shown in Formula 11. The reaction result was precipitated in ethylether/hexane (volume ratio is 1:9) as a semitransparent brown gel. Thesemitransparent gel was washed three times to remove monomers and thendried in vacuum at 40° C. for 24 hours to obtain product mPEG-PNLA. TheUV transmittance related to temperature is shown in FIG. 25.

Example 7 Copolymer of Methoxy Endcapped Polyethylene Glycol andLactide/γ-Butyrolactam Random Copolymer, Hereinafter mPEG-PPDLA

9.12 g of methoxy endcapped polyethylene glycol (mPEG, Molecular weightis 550 g/mol), 20.31 g of lactide, and 3 g of γ-butyrolactam weresubsequently charged in an anhydrous reactor, and the reactortemperature was slowly increased until the substances were totallydissolved. The temperature was continuously increased to 160° C., and12.97 μL stannous catalyst (stannous 2-ethylhexanoate) was added in thereactor to process polymerization at 160° C. for 8 hours. The reactionis shown in Formula 12. The reaction result was precipitated in ethylether/hexane (volume ratio is 1:9) as a semitransparent brown gel. Thesemitransparent yellow gel was washed three times to remove monomers andthen dried in vacuum at 40° C. for 24 hours to obtain productmPEG-PPDLA. The UV transmittance related to temperature is shown in FIG.25

Example 8 Copolymer of Methoxy Endcapped Polyethylene Glycol andLactide/(−)-2-Oxo-4-Thiazolidinecarboxylic Acid Random Copolymer,Hereinafter mPEG-POTLA

4.81 g of methoxy endcapped polyethylene glycol (mPEG, Molecular weightis 550 g/mol), 9.79 g of lactide, and 2.5 g of(−)-2-Oxo-4-thiazolidinecarboxylic acid were subsequently charged in ananhydrous reactor, and the reactor temperature was slowly increaseduntil the substances were totally dissolved. The temperature wascontinuously increased to 180° C., and 6.838 μL stannous catalyst(stannous 2-ethylhexanoate) was added in the reactor to processpolymerization at 180° C. for 8 hours. The reaction is shown in Formula13. The reaction result was precipitated in ethyl ether/hexane (volumeratio is 1:9) as a semitransparent brown gel. The semitransparent yellowgel was washed three times to remove monomers and then dried in vacuumat 40° C. for 24 hours to obtain product mPEG-POTLA. The UVtransmittance related to temperature is shown in FIG. 25.

Example 9 Copolymer of Methoxy Endcapped Polyethylene Glycol andLactide/(4R)-(−)-2-Thioxo-4-Thiazolidinecarboxylic Acid RandomCopolymer, Hereinafter mPEG-PTTLA

2.31 g of methoxy endcapped polyethylene glycol (mPEG, Molecular weightis 550 g/mol), 4.59 g of lactide, and 1.3 g of(4R)-(−)-2-Thioxo-4-thiazolidinecarboxylic acid were subsequentlycharged in an anhydrous reactor, and the reactor temperature was slowlyincreased until the substances were totally dissolved. The temperaturewas continuously increased to 180° C., and 3.277 μL stannous catalyst(stannous 2-ethylhexanoate) was added in the reactor to processpolymerization at 180° C. for 8 hours. The reaction is shown in Formula14. The reaction result was precipitated in ethyl ether/hexane (volumeratio is 1:9) as a semitransparent brown gel. The semitransparent browngel was washed three times to remove monomers and then dried in vacuumat 40° C. for 24 hours to obtain product mPEG-PTTLA. The UVtransmittance related to temperature is shown in FIG. 25.

Example 10 Copolymer of Methoxy Endcapped Polyethylene Glycol andLactide/DL-N-Acetylhomocysteine Thiolactone Random Copolymer,Hereinafter mPEG-PACTLA)

9.04 g of methoxy endcapped polyethylene glycol (mPEG, Molecular weightis 550 g/mol), 18.09 g of lactide, and 5 g of DL-N-Acetylhomocysteinethiolactone were subsequently charged in an anhydrous reactor, and thereactor temperature was slowly increased until the substances weretotally dissolved. The temperature was continuously increased to 160°C., and 12.86 μL stannous catalyst (stannous 2-ethylhexanoate) was addedin the reactor to process polymerization at 160° C. for 8 hours. Thereaction is shown in Formula 15. The reaction result was precipitated inethyl ether/hexane (volume ratio is 1:9) as a semitransparent yellowgel. The semitransparent brown gel was washed three times to removemonomers and then dried in vacuum at 40° C. for 24 hours to obtainproduct mPEG-PACTLA. The UV transmittance related to temperature isshown in FIG. 25.

Example 11 Copolymer of Methoxy Endcapped Polyethylene Glycol andLactide/5-Thiazolecarboxaldehyde Random Copolymer, HereinaftermPEG-PTCALA)

2.384 g of methoxy endcapped polyethylene glycol (mPEG, Molecular weightis 550 g/mol), 5.09 g of lactide, and 1 g of 5-Thiazolecarboxaldehydewere subsequently charged in an anhydrous reactor, and the reactortemperature was slowly increased until the substances were totallydissolved. The temperature was continuously increased to 160° C., and3.394, stannous catalyst (stannous 2-ethylhexanoate) was added in thereactor to process polymerization at 160° C. for 8 hours. The reactionis shown in Formula 16. The reaction result was precipitated in ethylether/hexane (volume ratio is 1:9) as a semitransparent yellow gel. Thesemitransparent yellow gel was washed three times to remove monomers andthen dried in vacuum at 40° C. for 24 hours to obtain productmPEG-PTCALA. The UV transmittance related to temperature is shown inFIG. 25.

Comparative Example 1 Copolymer of Methoxy Endcapped Polyethylene Glycoland Lactide, Hereinafter mPEG-PLA

17.36 g of methoxy endcapped polyethylene glycol (mPEG, Molecular weightis 550 g/mol) and 50 g of lactide were subsequently charged in ananhydrous reactor, and the reactor temperature was slowly increaseduntil the substances were totally dissolved. The temperature wascontinuously increased to 160° C., and 34.0 μL stannous catalyst(stannous 2-ethylhexanoate) was added in the reactor to processpolymerization at 160 for 8 hours. The reaction is shown in Formula 17.The reaction result was precipitated in ethyl ether/hexane (volume ratiois 1:9) as a semitransparent gel. The semitransparent gel was washedthree times to remove monomers and then dried in vacuum at 40° C. for 24hours to obtain product mPEG-PLA.

The mPEG-PLA solution viscosity was measured as shown in FIG. 26. Evenif the solution was heated to 45° C., the solution viscosity does notremarkably change. Accordingly, the lactone is necessary to copolymerizewith the lactide for completing the hydrophobic segment. If thehydrophobic segment is only polymerized by lactide, the diblockcopolymer composed of methoxyendcapped polyethylene glycol andpolylactide will not have thermosensitivity.

While the invention has been described by way of example and in terms ofthe preferred embodiments, it is to be understood that the invention isnot limited to the disclosed embodiments. To the contrary, it isintended to cover various modifications and similar arrangements (aswould be apparent to those skilled in the art). Therefore, the scope ofthe appended claims should be accorded the broadest interpretation so asto encompass all such modifications and similar arrangements.

1. A biodegradable copolymer, having a general formula:A—B; wherein A is a hydrophilic segment, having a general formula:

R₁ is C₁₋₈ alkyl; R₂ is ethyl, C₁₋₈ alkyl ethyl, C₁₋₈ alkoxyl ethyl, orcombinations thereof; and n is an integer of 5-20; and wherein B is ahydrophobic segment, having a general formula:

R₃ is hydrogen or methyl; R₄ is a linear saturated or unsaturated C₂-C₅alkanediyl group comprising one or more hetero atoms including O, S orN, branched or cyclic, saturated or unsaturated C₃-C₅ alkanediyl groupcomprising one or more hetero atoms including O, S or N; J is C═O, C═S,C—CHO, C═NH, or C═NR₅, wherein R₅ is C₁-C₃ alkyl group; K is S, C—CHO,NH, or NR₆, wherein R₆ is C₁-C₃ alkyl group; x is an integer of 5-20; yis an integer of 5-20; and x is greater than or equal to y.
 2. Thebiodegradable copolymer as claimed in claim 1, wherein the hydrophilicsegment A has a molecular weight of 300 to
 1000. 3. The biodegradablecopolymer as claimed in claim 1, wherein the hydrophobic segment B has amolecular weight of 800 to
 2000. 4. The biodegradable copolymer asclaimed in claim 1, wherein x and y has a molar ratio of 50:50 to 90:10.5. A thermosensitive material, comprising: water; and the biodegradablecopolymer as claimed in claim 1 dissolved in the water to form asolution, wherein the hydrophobic segment B aggregates to form micelles.6. The thermosensitive material as claimed in claim 5, wherein thebiodegradable material and the water have a weight ratio of 2:98 to40:60.
 7. The thermosensitive material as claimed in claim 5, whereinthe biodegradable material and the water have a weight ratio of 15:85 to30:70.
 8. The thermosensitive material as claimed in claim 5, whereinthe micelles have a diameter of 5 nm to 500 nm.
 9. The thermosensitivematerial as claimed in claim 5, further having a phase transfertemperature of 25 to 50° C.
 10. The thermosensitive material as claimedin claim 5, further having a phase transfer temperature of 30 to 40° C.11. The thermosensitive material as claimed in claim 5 is appliedthrough injection, pastille, powder, gel, solution, or oral liquid.